Gamma-secretase protein complex (γ-secretase)

The Gamma-secretase protein complex is a multi-subunit intramembrane-cleaving aspartyl protease that plays a critical role in various signaling pathways and protein processing events (UniProt, 2023). It is composed of four essential subunits: presenilin (the catalytic core), nicastrin, anterior pharynx-defective 1 (APH-1), and presenilin enhancer 2 (PEN-2) (PubMed: 28826486). The complex is best known for its role in the sequential cleavage of the amyloid precursor protein (APP) to generate amyloid-beta (Aβ) peptides, which aggregate into plaques in Alzheimer's disease (Nature Reviews Molecular Cell Biology, 2012). Additionally, it cleaves the Notch receptor, releasing the Notch intracellular domain (NICD) to regulate cell fate decisions and development (Genetics, 2017). Because of its central role in Aβ production, it has been a major therapeutic target for Alzheimer's disease, though many inhibitors failed due to off-target Notch toxicity (PubMed: 24651992). More recently, gamma-secretase inhibitors like nirogacestat have found success in treating certain cancers and desmoid tumors by blocking Notch-driven proliferation (FDA, 2023). Therapeutic strategies now focus on gamma-secretase modulators (GSMs) that selectively reduce toxic Aβ42 without interfering with Notch signaling (PubMed: 21857658).

Other names

Presenilin complexGSECGamma-secretase

Inhibition of the proteolytic activity of the complex to prevent the formation of amyloid-beta peptides or to block Notch signaling; or modulation of the cleavage site to shift production toward shorter, less toxic amyloid-beta isoforms (PubMed: 21857658).